3,4-dihydro-2-(2-hydroxy)ethyl-1-(r-amino)-pyrazino(1,2-b)-1,2-benzothiazin-11(2h)-one 6,6-dioxides

ABSTRACT

THE COMPOUNDS HEREIN ARE 3,4-DIHYDRO-2-(2-HYDROXY) ETHYL-1-(R-AMINO)-PYRAZINO(1,2-B)-1,2-BENZOTHIAZIN-11 (2II)-ONE 6,6-DIOXIDES, USEFUL AS ANTI-INFLAMMATORY AGENTS AND FOR OTHER, PHARMACOLOGICAL PROPERTIES.

United States Patent 3 787 398 3,4-DIHYDRO-2-(Z-HYHROXYETHYL-l-(R-AMINO) PYRAZINO[1,2-b] 1,2 BENZOTHIAZIN-HQLD- ONE 6,6-DIOXIDES Chris Royce Rasmussen, Ambler, Pa., assignor to McNeil Laboratories, Inc. No Drawing. Filed Oct. 2, 1972, Ser. No. 294,116 Int. Cl. (307d 93/02 US. Cl. 260-243 R 4 Claims ABSTRACT OF THE DISCLOSURE The compounds herein are 3,4-dihydro-2-(2-hydroxy) ethyl 1 (R-amino)-pyrazino[l,2-b]-1,2-benzothiazin-11 (21 E[ )-one 6,6-dioxides, useful as anti-inflammatory agents and for other pharmacological properties.

This invention relates to novel benzothiazin-ll-one 6,6- dioxides and, more particularly, to certain 3,4-dihydro-2- (2 hydroxy)ethyl-1-(R-amino)-pyrazino[1,2b]-1,2-benzothiazin-11(21 3 )-one 6,-6-dioxides and the preparation thereof. These novel compounds may be structurally represented as follows:

it t

S02 V (I) wherein R is a member selected from the group consisting of hydrogen, loweralkyl, diloweralkylaminoloweralkyl, aralkyl, and substituted aralkyl.

As used herein, lower alkyl and lower alkoxy may be straight or branched chained saturated hydrocarbons having from 1 to about carbon atoms, such as, methyl, ethyl, propyl, isopropyl, butyl, pentyl, sec-butyl, and the like alkyls, and, respectively, the corresponding alkoxys, such as methoxy, ethoxy, propoxy, isopropoxy, and the like. The term aralkyl preferably means a phenyl lower alkyl, such as, for example, benzyl, phenethyl, and the like.

The term substituted aralky preferably means an aralkyl, as previously defined, substituted with one or more members selected from the group consisting of halo, loweralkyl, and loweralkoxy, such as, for example, 2- bromophenethyl; 2,6-dichlorophenethyl; 4-methoxyphenethyl; 3,4-diethoxyphenethyl; 3-methyl-4-methoxyphenethyl; 2 chlorobenzyl; 2,6-dibromobenzyl; 4-ethoxybenzyl; 3,4-dimethoxybenzyl; 3-methyl-4-methoxybenzyl; and the like. As used herein, halo means fiuoro, chloro, bromo, and iodo.

The compounds of Formula I are prepared by reacting (1,2,3,4 tetrahydro 11-hydroxy-1-oxopyrazino[1,2-b]- l,2-benzothiazin-2-yl)ethyl methanesulfonate 6,6-dioxide (II) with a large molar excess of aqueous ammonia (for R=H) or with a 1-2 molar excess of an appropriate amine of formula H NR (for RiH) dissolved in a suitable organic solvent such as a lower alkanol, e.g., methanol, ethanol, propanol, isopropanol, and the like; an ether, e.g., ethyl ether, tetrahydrofuran, dioxane, and the like; a chlorinated lower alkane, e.g., dichloromethane, chloroform, carbon tetrachloride, and the like; an aromatic hydrocarbon, e.g., benzene, toluene, xylene, and the like; dimethylsulfoxide; dimethylformamide; and the like. Elevated temperatures may be favorably employed in the reactions with amines.

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The foregoing reaction may be illustrated by the following:

OH (H) N-CHzCHzO S O zcHa solvent N RNH: S03

A second method of preparing the compounds of this invention (for RiH) is by reaction of 2,3,5,6-tetrahydro- 13H oxazolo[2,3':3,4]py razino[1,2-b]-1,2-benzothiazin- 13-one 8,8-dioxide (III) with one molar equivalent of an appropriate primary amine of formula H NR in a similar solvent to those described above. Again, elevated temperatures may be employed. This second method may be illustrated by the following:

O.. t I j UY (III) The starting compounds of Formulas II and III are described in my copending application Ser. No. 294,126, entitled Novel 1,2-Benzothiazine Dioxides and Precursors Therefor, filed on the same date as the instant application.

The Compounds I of this invention are useful for their pharmacological properties. They have been observed to possess anti-inflammatory activity as demonstrated in the conventional kaolin-induced rat paw edema assay when orally administered at doses of about 100 mg./kg. body weight. For example, when R=H, 14-37% inhibition is observed; when R=CH 20-44% inhibition is observed; and when R=CH CH C H 832% inhibition is observed.

Selective enzyme inhibition in vitro has also been observed for the subject Compounds I. For example, when R=CH CH C H inhibition of tyrosine hydroxylase and histidine decarboxylase at a concentration of about 0.001 molar is observed. In addition, hypotensive activity has also been observed. For example, when R=H, oral doses of about 50 mg./kg. body weight in the unanesthetized dog and i.v. doses of 5-10 mg./kg. body weight in the anesthetized dog have been observed to cause a decrease in blood pressure, generally on the order of about 35 mm. Hg and 40100 mg. Hg, respectively, for a period of greater than one hour.

The following examples are intended to illustrate, but not to limit, the scope of the present invention.

EXAMPLE I 1 amino 3,4 dihydro-Z-(2-hydroxy)ethylpyrazino [1,2-b]-1,2-benzothiazin-ll-one 6,'6-dioxide.-To 0.5 1. of rapidly stirred 28% aqueous ammonia is added 58.26 g. (0.15 mole) of 1,2,3,4-tetrahydro-1l-hydroxy-l-oxopyrazino 1,2-b] 1 ,Z-benzothiazin-Z-yl) ethyl methanesulfonate 6,6-dioxide. The resulting suspension is stirred for several hours at ambient temperatures, at the end of which time the product is collected, washed with water, and dried. Fractional crystallization of this product from methanol and chloroform-% ethanol yields the desired product, 1 amino-3,4-dihydro-2- (2-hydroxy) ethylpyrazino 1,2-b] 1,2 benzothiazin-ll-one 6,6-dioxide, M.P. 204-206 C dec.

Analysis.Calod. for C H N O S (percent): C, 50.47; H, 4.89; N, 13.58; S, 10.37. Found (percent): C, 50.32; H, 4.99; N, 13.53; S, 10.35.

solvent RNH:

3 EXAMPLE :1

3,4 dihyro-2-(2-hydroxy) ethyl-l-rnethylaminopyrazino [1,2-b] 1,2-benzothiazin-11(2' I I )-one -6,6-dioxide.--T0 about 100 ml. of a saturated solution of anhydrous methylamine in dimethylformamide is added 20.0 g. (0.0515 mole) of (1,2,3,4 tetrahydro-ll-hydroxy-l-oxopyrazino [1,2-b]-1,2-benzothiazin-2-yl)ethyl methanesulfonate 6,6- dioxide. After solution is complete, the solution is again saturated with methylamine and is then warmed on a steam bath for 1.5 hours. After the solution has stood for about 15 hours, the solvent and excess amine are removed in vacuo, water is added to the residue, and the resulting solid is collected. Recrystallization from acetone-water yields the pure product, 3,4-dihydro-2-(2-hydroxy)ethyl-1- methylaminopyrazino 1,2-b] 1,2-benzothiazin-l 1 (21:1) one 6,6-dioxide, M.P. 174-175 C.

Analysis.-Calcd. for C H N O S (percent): C, 52.00; H, 5.30; N, 12.99. Found (percent): C, 51.93; H, 5.33; N, 12.37, 13.32.

EXAMPLE III 3,4 dihydro 2 (2-hydroxy)ethyl-l-(fi'phenethynaminopyrazino{1,2-b] 1,2 benzothiazin-l l-one 6,6-dioxide.--To 1.0 g. (0.0033 mole) of 2,3,5,6-tetrahydro- 13E oxazolo[2',3':3,4]pyrazino[1,2-b]-1,2-benzothiazin- 13-one 8,8-dioxide in 15 m1. of dimethylformamide is added 0.4 g. (0.0033 mole) of fl-phenethylamine. The mixture is heated on the steam bath for two hours and is then allowed to stand for about 15 hours. After the solvent has been removed in vacuo, the residue is triturated with acetone to yield the product, 3,4-dihydro-2-(2-hydroxy)ethyl 1 (fi-phenethynaminopyrazinoij1,2-b]-1,2- benzothiazin-ll-one 6,6-dioxide, M.P. 144-146 C.

Analysis.--Calcd. for C H N O S (percent): C, 61.00; H, 5.61; N, 10.16; S, 7.76. Found (percent): C, 60.97; H, 5.66; N, 10.17; S, 7.75.

EXAMPLE IV 1 ethylamino 3,4-dihyro-2-(2-hydroxy) ethylpyrazino [1,2-b] -1,2-benzothiazin-1 1 211) -one 6,'6-dioxide.-To a solution of 11.3 g. (0.25 mole) of anhydrous ethylamine in 100 ml. dimethylformamide is added 20.0 g. (0.0515 mole) of (1,2,3,4-tetrahydro-1l-hydroxy 1 oxopyrazino [1,2-b] 1,2-benzothiazine-2-yl)ethyl methanesulfonate '6,6-dioxide. After solution is complete, the whole is warmed for several hours on a steam bath and is then allowed to stand for about 15 hours. After the solvent and excess amine have been removed in vacuo, water is added to the residue, and the resulting product, l-ethylamino- 3,4 dihydro-Z-(Z-hydroxy)ethy1pyrazino[1,2-b]-1,2-benzothiazin-11(2' El)-one 6,6-dioxide, is collected and recrystallized from acetone-water.

EXAMPLE V l n-butylamino-3,4-dihydro-2-(2-hydroxy)ethylpyrazino[1,2-b] 1,2-benzothiazin-11-one 6,6-dioxide is obtained by repeating the procedure of Example IV except that an equivalent amount of n-butylamine is substituted for the ethylamine used therein.

EXAMPLE VI l-benzylamino 3,4 dihydro-2-(2-hydroiiy)ethylpyrazino[1,2-b-]-benzothiazin-11-one 6,6-dioxide is obtained 'by repeating the procedure of Example 1V except that an equivalent amount of benzylamine is substituted for the ethylamine used therein.

EXAMPLE VII 1-(3-dimethylaminopropy1)amino 3,4 dihydro-2-(2- hydroxy)ethy1pyrazino[1,2-b] 1,2 benzothiazin-l l-one 6,6-dioxide is obtained by repeating the procedure of Example IV except that an equivalent amount of 3-dimethylaminoprop'ylamine is substituted for the ethylamine used therein.

4 EXAMPLE vm The procedure of Example III is repeated except that an equivalent amount of each of the following substituted phenethyl amines:

4-bromo-fi'-phenethylamine; 2, 6-dich1oro- 3-phenethylamine; 4-methoxy- 3-phenethylamine; 3,4-diethoxy-B-phenethylamine; and 3-methyl-4-methoxy-B-phenethylamine is substituted for the unsubstituted fi-phenethylamine used therein to yield, as respective products, the following compounds:

1- (4-bromo-fi-phenethylamino) -3,4-dihydro-2- (2-hydrox'y)ethylpyrazino [1,2-b]-1,2-benzothiazin-11- one 6,6-dioxide;

1-(2,6-dichloro-e-phenethylamino -3,4dihydro-2- (2- hydroxy) ethylpyrazino[ 1,2-b] -1,2-benzothiaziui1 l-one 6,6-dioxide;

3,4-dihydro-2- Z-hydroxy)ethyl-1-(4-methoxy-fiphenethylamino) pyrazino [1,2-b] benzothiazinl1 l-one 6,6-dioxide;

1- 3,4-diethoXy-B-phenethylarnin0) -3,4-dihydro-2- (2- hydroxy)ethylpyrazino[1,2-b]-1,2-benzothiazinll-one 6,6-dioxide; and

3 ,4-dihydro-2- Z-hydroxy )ethyl-1-( 3-methyl-4- methoxyfi-phenethylamino) pyrazino[ 1,2-b] -l ,2- benzothiazin-lil-one 6,6-dioxide.

EXAMPLE 1X The procedure of Example III is repeated except that an equivalent amount of each of the following substituted benzylamines:

Z-chlorobenz'ylamine; 2,6-dibromobenzylamine; 4-ethoxybenzylamine; 3,4-dimethoxybenzylamine; and 3-methyl-4-methoxybenzylamine is substituted for the B-phenethylamine used therein to yield, as respective products, the following compounds:

wherein R is a member selected from the group consisting of hydrogen, loweralkyl, diloweralkylaminoloweralkyl,

5 6 benzyl, benzyl substituted with one to two members seethyl)aminopyrazino[1,2-b]-benzothiazin-11 one 6,6 -dilected from the group consisting of halo, loweralkyl and oxide.

loweralkoxy, phenethyl, and phenethyl substituted with References Cited one to two members selected from the group conslstlng of UNITED STATES PATENTS halo, loweralkyl and loweralkoxy.

2. 1 amino 3,4 dihydro 2 (2 hydroxy)ethy1- 5 3,408,347 10/1968 Shavel et a1. 260243 pyrazino[1,2-b]-1,2-benz0thiazin-1l-one 6,6-dioxide.

3:. 3,4 qih 2 (2 hydrqxyzethyl 1 methyl: JOHN M. FORD, Pnmary Exammer agarzopyrazmoHJ-N-LZ benzothlazm ll-one 6,6 d1- Us. Cl. XR.

4. 3,4 dihydro 2 (2 hydroxy)ethyl 1 (p phen- 424246 

